Talk at Harlem Biospace 10/20/14 Ron Guido

1. FDA Applications in a Nutshell

2. “Good science and good regulatory practice often part
company” …..*
*(sometimes..) park the science and follow the rules

3. Some Thoughts on “FDA in a nutshell”
(??)
•• Perceived as Formulaic
…
• In Reality
– Program Specific
– Remains Subject to
Change
– Often unpredictable
– Risky
– Subject to “intangibles”
– Failure prone

4. Development Landscape
• Biopharma development – among the most
highly regulated of any commercial activity
• Sheer Number of Regulations = complexity
• Even well- run, and compliant programs fail
• Program risk has discouraged innovation
• Understanding the intangibles mitigates risk

5. Changing Scope of Development
• Pharmaceutical development is now
conducted to facilitate GLOBAL approval
– Pharmaceutical products are “similarly” regulated
in essentially every country.
– Most countries have their own health authorities
with individual “personalities”
– Regulations are applicable to both the
investigation and marketing of compounds.
Intangibles a critical facet of complexity
5

6. Drug Development is (deceptively) formulaic
• Find a compound with activity
• Chemically define it (characterize)
•• Explore its basic pharmacology and toxicology
• Define safety and efficacy via clinical research
• Develop a dosage form
• Compile data and file for approval
• Wait patiently..
Same formula for years --- why study and
strategize the process
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7. Regulatory Framework
• Regulations are complex systems of
interrelated rules
• Govern both development and post
approval activities
• Continuously undergoing amendment and
supplementation
• Intended to assure that products are
safe (do no harm) and effective ( do
some good)
•• Most have arisen from adversity
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8. US Base Standards for Drugs / Biopharmaceutic Approval
• Products must be recognized as safe
•• Product must be demonstrated to be effective
– 2 adequate and well controlled trials
• Benefits of use must always outweigh potential
risk
• Identified risks must be mitigated
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9. Why we (over)Regulate
• All Regulation grew out of adversity
– Proven Safety counters impure, adulterated, unsafe
• Elixir of Sulfanilamide
• Thalidomide
– Proven Efficacy counters worthless ““cure alls””
• Snake oil
• Medicine shows

10. Development Metrics
• 1 in 1000 candidates make it to phase 1 clinical trial
• 8 to 15 years to develop a new drug/biologic product
• $802 million spent before the medicine is available for sale
• When failures are factored in (not a rare occurrence), Avg. costs
exceeds $ 5 billion per drug
• 2012 :Nature Reviews Drug Discovery
–– Number of drugs invented per billion dollars of R&D reduced by
half every 9 years
• Attention to early development, successful execution of significant
clinical studies helps to reduce number of development failures.
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11. Approval Outcomes and Costs
• 400+ Medications Approved in 2000 -2012
• 35 Approved in 2012
• Current Development Time: 10 – 15 years
• Medicines in Development
– 1999 – 1,800
– 2009 – 2,900
– 2013 - 3,400
– 40% increase since 2005
• Total Development Costs ($), factoring failure
– 1975 – 138 mio
– 1987 – 318 mio
– 2001 – 802 mio
– 2006 – 1.318 billion
– 2012 – 5.0 billion
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12. Risky…

13. ..its also complex

14. Drug Development: Changing Landscape To Reduce Risk
• Targeted
• Outcome / patient focused
– Defined Outcome
– Best Population
– Measurable effect
– TRUE Clinical Effectiveness
– Anticipated Risk / Benefit
– Mitigated Risks
• US Approvals Up in 2011 & 2012
– Most approved first pass
– Application Quality = Shared Sponsor execution
• FDA Remains unpredictable -- Congressional
Oversight remains high

15. So what’s a drug ?
Drug describes [any] articles intended for use in
the diagnosis, cure, mitigation, treatment, or
prevention of disease in man or other animals.
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16. What is a “new” drug
• The regulatory definition of "new drug“ is critical as it establishes
both the need for, and requirements for approval
A Ne • New Drug is an active substance which is not generally
recognized, among experts qualified to evaluate the safety and
effectiveness of drugs (FDA), as safe and effective for use under
the conditions prescribed, recommended, or suggested in the
labeling thereof
• Approved via IND/NDA
• Active compounds recognized under the Food and Drugs Act of
June 30, 1906 are the exception [“Old Drug”]
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17. Development Gating – Best Practice
low “probability of success” compounds get “pushed
along” by inertia
To mitigate this risk candidate compounds are
typically “gated”
Pre-specified criteria are established to prevent
blindly moving products along

18. General Development Gating

19. Gated Approaches to Regulated Development
• Target Identification
• IND Enabling Activities
•• IND Filing
• NDA Filing
• Postapproval Actions

20. Candidate Definition – General Investigational
Plan
A Priori….
•• Define intended Indication
• Define target population
• Determine Optimal Dosage form
• IP / Exclusivity Assessment
• Develop Global Regulatory Strategy

21. Strategic Approaches to Development
• Target Identification
– Clinically meaningful
– Commercially attractive
– Measurable effect

22. Initiation of clinical investigation of Target
Virtually everything is hinged off clinical studies
Problem: How to administer an unapproved drug to
a human for testing
• US: IND – Investigational New Drug (Application)
• EU: CTA – Clinical Trial Authorization
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23. IND Defined
• IND - Investigational New Drug (Application)
– Documentation submitted to and accepted by FDA before new drug can be
shipped interstate for human testing.
–– IND includes all evidence that studies can be done with reasonable safety
to subject/patient.
– Following initial filing, becomes repository for all subsequent amendments,
protocols, preclinical/ clinical data
• CTA - Clinical Trial Application
– EU version of US IND
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24. So…When do I need an IND
• New Drug
• Old Drug –New indication
•• New Patient population
• New manner of use significantly different from
the approved label

25. Strategic Approaches to Development
• Target Identification
– Clinically meaningful
– Commercially attractive
• I–NMeDasu raEble neffeact bling Activities
– Preclinical Pharmacological
Characterization – Proof of Concept
– Preclinical Tox Characterization –
Proof of Safety
–Chemistry and Manufacturing
– Clinical Development Plan
– PK Characterization – Metabolism,
Fate
– Target Indication Definition
• Measure

26. IND Development: Drug Substance - API
• Synthesis
• Reliable supply
•• Quality of Supply – Reproducibility
• Stability
• Impurities

27. IND Development : Preclinical Pharmacology
• Proof of Concept
• Mechanism of Action
•• Target
• Characterisation of possible “class”off target
effects
• Absorbtion
• Distribution
• Metabolism
• Excretion

28. IND Development : Preclinical Toxicology
• Genotox
• Cellular Toxicities
•• Whole Animal Studies
• Tox Characterisation of major impurities and
metabolites
• Threshold toxicity to enable investigational study
(i.e.

29. Gating: Filing Readiness - IND
• You have a compound with a justified proof of
concept
•• You have conducted the minimal required animal
toxicology testing
• You have a dosage form that is chemically
characterized
• The dosage form has demonstrated stability for
the proposed duration of initial clinical testing
• To initiate testing of safety and efficacy in
humans..you need to open an IND….

30. Strategic Approaches to Development
• Target
• (Pre-IND Meeting)
• IND Filing
– Chemical Characterization (API, DPI) to
support Clinical Development
– Protocol/Investigator/Clinical Development
Plan
– Phase 1 : Gross Safety
– Phase 2 : Dose Finding / Optimization
– Phase 3 : Pivotal Trials (2)
• Measure

31. IND Support: Initiation of Clinical (Trials)
• Enabling work Complete
• IND filed and “may proceed”
•• Clinical Dosage Form Developed
• Stability Consistent with longest proposed trial
• Clinical packaging
• Clinical Trials
– Phase 1
– Phase 2
– Phase 3
– Phase 4

32. Clinical Research Basics
• Clinical Development Plan (volatile..)
– Established Protocol
– Qualified Investigator
– Prospective Analysis Plan….
• Phase 1: safety of product in small numbers of
healthy volunteers (n=20-80)
• Phase 2: efficacy and safety in small number of
patients with target indicated condition – dose
range finding (n =100 – 300)
• Phase 3: Pivotal market enabling trials – Safety
and efficacy compared to PBO and/or standard of
care (n = 1,000 – 3,000)
• Phase 4: Postmarketing Studies

33. A word on endpoints
• Proper choice of endpoint (or outcome measured
following intervention) is PIVOTAL
• A primary efficacy endpoint must be something
that has a substantial impact on the course of the
target disease, and the patient’’s well-being
• There needs to be a validated way to measure
this outcome

34. Clinical Stage Gating
• Phase 1 – no untoward effects, acceptable
kinetics
•• Phase 2 – Supports dose selection
• Phase 3 – Supports S&E in endpoints related to
intended indication, and in target patient
population

35. Pre NDA
• CMC full scale up and final production process
validation
•• Container / Closure
• Shelf life supporting stability
• Proposed labeling
• Agreement on data sets to be presented and
manner of presentation

36. Strategic Approaches to Development
• NDA Filing
– Chemistry / Manufacturing Scale Up
–– Preclinical Analyses
– Clinical Analyses (safety, efficacy)
– Integrated Analysis -- Labeling
• Postapproval Actions
– Risk Mitigation
– Post approval Measure

37. Marketing Approval Applications
• MAA – Marketing Authorization Application - EU
– Registration documents seeking approval to market
a drug product Ex-US. A general term for
registration document. In EU, the MAA implies a
document used for multi-national submission as
opposed to seeking approval in one specific
country.
• NDA – New Drug Application - USA
– Registration document seeking approval to market
a drug product (NOT biological product).
• BLA – Biological License Application – USA
– Think NDA for a biological drug product.
– Heavily focused on process
37

38. Marketing Approval Applications
US
• NDA – New Drug Application
– 505(b)(1),
– 505(b)(2),
– 505(j) ANDA - Abbreviated New Drug Application
•• BLA – Biologic License Application
EU
• MAA – Marketing Authorization Application
• CTD – Common Technical Document;
– Harmonized common format for organization of information in
marketing authorization (registration) applications.
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39. Endgame: Label Development
• Label—The label is the document physically attached
directly to the packaging materials that are in direct
contact with the excipient, drug substance, or drug
product.
• Labeling—Labeling includes the label and the
documents included with, but not attached to, the
packaging materials that are in direct contact with the
excipient, drug substance, or preparation (e.g.,
package insert).
Label and labeling define the claims made for the drug
product in terms of the target for use and the intended
patient population
It is directly substantiated by the integration of all
clinical data
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40. Strategic Approaches to Development
• Target Identification
– Analysis -- Labeling
• Postapproval Actions
– Risk Mitigation
– Post approval Measure

41. Schematic of FDA Development and
Review

42. NDA Review Steps Simplified
• Preclinical (animal) testing is completed.
• API and DP is initially characterized
• Pre IND Meeting held.
• Investigational new drug application (IND) supports
initiationof human testing in clinical trials.
• Chemistry and Manufacturing is further characterized
• Pre-NDA meeting held
• NDA Submission
• NDA Acceptance -- FDA has 60 days to decide
whether to file it so it can be reviewed.
• FDA “files” the NDA, an FDA review team is assigned
• The FDA reviews S/E information and adjudicates to
proposed professional labeling
• The FDA inspects the facilities where the drug will be
manufactured
• FDA approves application, or issue a complete
response letter.

43. Bumps in the Road
If FDA review supports the benefits of a drug
outweigh the known risks, the drug will receive
approval.
Common impediments:
• Unexpected safety issues
• Failure to demonstrate effectiveness.
• Need additional studies--more people, different types
of people, a longer period of time.
• Manufacturing issues.
• Drug for clinical trials does not match market product.
• Scale up, supplier or quality control issues
• MOST OFTEN a combination of problems that prevent
approval.
FDA outlines the justification for its decision in a
complete response letter to the drug sponsor.

44. Remember the intangibles…
• Drug /Biotech Development requires cutting edge
science, but that’s not all its about
• Regulation is supported by science, but science and
g pp y ,
l ti regulation ft often part t
company
• Industry and academic groups lead (and precede)
regulation
• Novelty lowers hurdles for approval, but often
complicates review process
• Product is defined (both) by its active, and the
associated claims of action
• Product needs to have a meaningful clinical effect
• Burden of proof is always on the sponsor
• Never, Ever, Forget the value of Regulator
relationship
44

45. Thoughts on Innovation Breakdown
• Promising drugs are not being developed because
of the expense and risk of developing them.
•• Promising acquisitions are not made because of
unacceptable/ un-evaluable Regulatory Risk
• The promise of great candidate products is being
obscured by focus of their presentation
• FDA is unpredictable and risk averse

46. Thoughts on Innovation Breakdown
• The only way to promote innovation is to de-risk
development
•• This will require new approached to
– Target Choice
– Testing Standards
– Data Collection
– Evaluation
• A “disruptive” approach to “de-Risk”

47. Innovation Risk influences Value Inflection Points
Development Stage Acquisition Cost
• Discovery
• $
• Proof of Concept
• $$
• First in Human
• End of Phase 2
• Pre-NDA
• $$$
• $$$$
• $$$$$
• Post Approval • $$$$$$$$$$

49. "It must be considered that there is nothing more difficult to
carry out, nor more doubtful of success nor dangerous to
handle, than to initiate a new order of things.
Niccolo Machiavelli, 1513